A milk fat globule membrane (MFGM), which is the membrane components of cow milk derived from lactating mammary-gland cell, is mainly composed of both lipids and proteins. For the pharmaceutical usefulness of MFGM, the preparation of 5% triolein emulsions were studied by use of MFGM, in comparison with various surfactants ; lecithin, HCO60, Polysorbate 80. These emulsions were examined by two type methods of preparations which were homogenization alone (type A) and that following by sonication (type B). The mean diameters of oil droplets were determined by centrifugal lift method, and the emulsifiability was evaluated by turbidimetry. It was observed that the mean diameters of the emulsions by type B were smaller about one-third than those of emulsions by type A. The stability of emulsions by type B was also extensively improved. Furthermore, MFGM was suggested to have a strong emulsifiability as well as those of synthetic emulsifiers. These results indicate that MFGM can be substituted as natural emulsifier for synthetic emulsifier for oral use.

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A newly developed drug delivery system, ultrafine particles of activated charcoal is introduced and 2 types of them are examied in absorbability of MMC and ability of transport of MMC to lymph system. One is Mitsubishi CH-40 and the others Mitsubishi 1500AA. The sizes of each prinary particle of them are about 20 nm in diameter. As for the absorbability concern, much better one is observed to MMC in 1500AA than in CH-40. Serial samplings of lymph of thoracic duct by canulation and serial blood samplings of peripheral vein are done in canine to know the dynamics of lymph-blood systems through those clearance curves of MMC. Clearance K and half value period T_1/2 are calculated from the formula ; C(t)=C(t₀)e^-kt. Comparing to that of MMC-saline, the activated charcoals are proved to have good abilities of transport MMC to lymph systems and in 1500AA charcoal, MMC is retained much longer time than in CH-40. Congestive effects of the lymph systems are observed by ligation of the thoracic duct in CH-40 with 25% prolong of T_1/2. In conclusion, these drug delivery systems are suitable for the targeting chemotherapy of lymphnodes metastasis of colorectal cancer, especially by 1500AA activated charcoal.

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In order to reduce the adverse effects of anticancer drugs, the new dosage form comprised activated carbon particles (Mitsubisi#1500AA^R, specially prepared by Mitsubisi Chemical Industries Co., Ltd, Tokyo, Japan) adsorbing aclarubicin was devised. The new dosage form composed of aclarubicin and activated carbon particles ten times as weighty as aclarubicin in saline. The acute toxicity of the new dosage form(ACR-CH) injected intraperitoneally was studied in mice. The LD₅₀ value of ACR-CH was over 75mg/kg in terms of aclarubicin, otherwise that of aclaruhicin aqueous solusion (ACR-sol) was 32.9mg/kg by means of Litchfield-Wilcoxon's method. Pathological examinations of the animal' organs and examinations about body weight change and symptom of toxicity revealed no remarkable difference between ACR-CH and ACR-sol. Those results show no evidence of any addisional side effects of aclarubicin by the change of dosage form. We concluded that acute toxicity of aclarubicin was reduced by the use of activated carbon particles as a carrier.

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New method to evaluate drug disposition characteristics in tumor was developed employing rat tissue-isolated Walker 256 carcinosarcoma perfusion system. Mitomycin C and its lipophilic and macromolecular prodrugs used as a prototype of targeting DDS were administered from the arterial side by bolus injection or constant infusion. By applying moment analysis and so on, disposition characteristics of these drugs in tumor were elucidated and discussed in relation to their physicochemical properties, These experimental system was thus suggested to be useful in evaluating drug disposition in tumor.

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The chemotherapeutic anticancer agent cisplatin (cis-diamminedichloroplatinum, CDDP) has several disadvantages, such as its extreme nephrotoxity and rapid binding to plasma proteins, and also poor penetration in the central nervous system, Liposomes therefore seemed to be suitable carriers to overcome these problems. Liposomes were investigated as a carrier for the delivery of therapeutic agents to target brain tumors. Four kinds of liposomes were prepared : neutrial liposome (phosphatidylcholine and cholesterol), positively charged liposome (added stearyl amine), negatively charged liposome (added phosphatidic acid) and neutral liposome with low membrane fluidity (dipalmitoylphosphatidylcholine and cholesterol). As for the uptake of radioactivity in the brain tumor, spleen, liver, kidney and brain 30 minutes after the injection of liposomes labeled with ¹⁴C into the 9L cells implanted brain tumor rats, the spleen had the highest uptake of radioactivity. The uptake was also greater in the brain tumor and lower in the kidney as compared to using cisplatin alone. The brain tumor uptake were in order of neutral liposome with low membrane fluidity, neutral liposome, negatively charged liposme and positively charged liposome. The cytotoxity of cisplatin against 9L-glioma cells was not decrease by encapsulation of liposomes. These results indicate that liposomesencapsulated cisplatin could be utilized for targeting the chemotherapy of brain tumors, however in order to increase the targetability of liposome to brain tumors, we have developed the coating of liposomes with a cell specific polysaccharide.

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We examined the stability of ofloxacin (OFLX) in the hydroxypropyl cellulose (HPC) solution, the viscosity and its antibacterial activity. The antibacterial agent polymer solution was formulated to use against inveterate root canal infections which were not relieved by conventional treatments, expected to perform sustained-release of the drug in the local area. The OFLX potency was maintained even in one year and a slight decrease of the viscosity (about 5% from original 450 cSt at 25°C) was observed. Little effect of HPC on the antibacterial activity was found against 21 bacterial strains examined which were collected from root canal and nearby. Ten patients with inveterate root canal infections were treated with the sustained-release medicament (OFLX-HPC) containing 0.5% of OFLX in the 2.25% HPC. A 50-100 μl of the drug solution was applied through a syringe needle into the infected channel once a week. The clinical effects were evaluated by scoring the disappearance of various symptoms such as spontaneous, occlusal and percussion pains, bleeding of root canal and pus discharge. The overall results were excellent in 5 patients, good in 4 patients and poor in one patient. No appreciable adverse reactions were observed for any patients.

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The solid complex of buserelin acetate (BLA) an agonistic analogue of luteinizing hormonereleasing hormone (LHRH), with heptakis (2, 6-di-O-ethyl)-β-cyclodextrin (DE-β-CyD) was prepared by the kneading method. The in-vitro release of BLA from the arachis oil suspension into the aqueous phase was significantly retarded by the complexation with hydrophobic DE-β-CyD. The oily suspensions can be readily injected subcutaneously into rats using a standard syringe without additives. A single subcutaneous injection of the oily suspension containing the BLA-DE-β-CyD complex at a dose of 1 mg/kg as BLA into rats provided a continuous plasma level of BLA for at least seven weeks, giving a mean residence time of BLA in plasma for the complex about seventy times longer than that for BLA alone. Furthermore, the pharmacological effect of BLA in rats, as indicated by a suppression of plasma testosterone levels to castrate, was sustained for at least one month when the complex was administered. These results support the possible use of DE-β-CyD as an injectable sustained-release type carrier for the chronic treatment of endocrine-dependent diseases with BLA.

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We evaluated the acute toxicity of a new dosage form (CDDP-ms) comprized cis-platinum loaded lactic acid oligomer micropheres following intraperitoneal administration in mice. The LD₅₀ value of CDDP-ms was 23.8mg/kg, which was 17.6% of the LD₅₀ value(13.5 mg/kg) of cis-platinum aqueous solution. Autopsy findings revealed no additional toxicity due to the change of the dosage form in to the microspheres.

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The effect of lysophosphatidylcholine (LPC) on intestinal absorption of carboxyfluorescein was studied in rat small and large intestines. We found that LPC markedly enhanced the absorption of CF in the large intestine as well as the small intestine in concentration-dependent manner, The minimum effective concentrations in the large intestine and the small intestine were 0.25% and 1.0% respectively, These results showed that LPC acted as strong absorption enhancer and was more effective on the large intestine than on the small intestine similarily to the other absorption enhancers.

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